By Craig Schneider, MD, and Erica Lovett, MD
Dr. Schneider is Director of Integrative Medicine, Department of Family Medicine, Maine Medical Center in Portland. Dr. Lovett is a Fellow in the Integrative Family Medicine Program at Maine Medical Center and University of Arizona (Tucson); they report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.
When last reviewed in this newsletter,1 two large negative studies had recently examined St. John’s wort (SJW), an herbal therapy for depression, casting doubt on its efficacy in the treatment of depression. Literature on efficacy, adverse effects, and particularly drug interactions of SJW continues to grow, as does controversy regarding its use.
History and Botany
St. John’s wort (Hypericum perforatum) is a perennial herb native to Europe, North Africa, and western Asia. It is now naturalized in Australia and the Americas where its bright yellow star-shaped flowers are often recognized along roads and fields. SJW is so named due to its coincident blooming in late June, when John the Baptist is said to have been born.
Its medical use dates back to the ancient Greeks, documented by Hippocrates, Dioscorides, and Galen. Thirteenth century medical texts listed SJW as Herba demonis fuga, “the herb that chases away the devil.”2 The Swiss physician Paracelsus reportedly used SJW to treat psychiatric disorders including depression and melancholy in the 16th century, while American Eclectic physicians prescribed it for treating “hysteria and nervous affections with depression.”3 In Europe, SJW remains among the most commonly used antidepressants, being prescribed in Germany nearly twice as commonly as all other antidepressants. Demand has led to large-scale cultivation in Europe, North and South America, Australia, and China.3
Mechanism of Action
St. John’s wort flowers, and to a lesser extent its leaves, yield multiple active constituents. The mechanism of action is not fully understood, but biologically active components include hyperforin, adhyperforin, hypericin, pseudohypericin, flavonoids, xanthones, and others.4 The two most relevant constituents appear to be hyperforin and adhyperforin. Because hypericin was formerly considered the active ingredient and products were standardized to its content, hyperforin and adhyperforin content probably varied significantly between products leading some to hypothesize this as an explanation for differences seen in the trials. Both hyperforin and adhyperforin appear to modulate the effects of serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA).5 Inhibition of interleukin-6 and increased cortisol production have also been reported.6 Clinical effects may be the result of a combined contribution of multiple mechanisms, each individually too weak to account for the action.7
Numerous trials have demonstrated that SJW is more effective than placebo and perhaps the equal of pharmaceutical antidepressants in the treatment of mild-to-moderate depression. Recent American trials, however, shed doubt on its effectiveness in more severe forms of depression.
Two large U.S. trials failed to show a benefit of SJW over placebo; this received significant media attention and piqued the interest of the medical community. The National Institutes of Health-sponsored Shelton et al trial compared SJW (Jarson 300 mg tid) to placebo for eight weeks in 200 outpatient subjects at 11 U.S. academic medical centers.8 After a one-week, single-blind run-in of placebo, participants were randomized to receive placebo (n = 102) or SJW (n = 98) 900 mg/d for four weeks. Initial non-responders’ doses were increased to 1,200 mg/d. There was significant improvement over eight weeks in both arms, and SJW was not superior to placebo in primary outcomes. SJW did produce a statistically significant greater remission rate than placebo (14.35% vs. 4.9%, respectively).
This was a rigorous and well-conducted trial but has been criticized for various reasons. The study enrolled subjects with chronic depression (average of more than two years). The study did, however, exclude those with a history of failing to respond to an antidepressant in the current episode or failing more than one trial of antidepressants in the past. This study also lacked an active control. A non-blinded follow-up study by this research group found that nonresponders openly treated with marketed antidepressants of the investigator’s choice for 24 weeks responded to treatment. The authors suggest this indicates their initial study did not contain a disproportionate treatment-resistant population, thus supporting lack of efficacy of SJW in the prior trial.9
Another U.S. trial sponsored by Pfizer and conducted at Duke University compared SJW (LI160 300 mg tid titrated up to 1,500 mg/d), sertraline (50-100 mg/d), and placebo in 340 patients with severe major depression over eight weeks.10 In the primary analysis (reduction of Hamilton-Depression scale [HAM-D] score), neither SJW nor sertraline improved depression scores more than placebo. On a secondary endpoint (Clinical Global Impressions Scale [CGIS]), sertraline was better than placebo.
The largest European double-blind, placebo-controlled, randomized, multicenter trial demonstrated that SJW (WS5570 300 mg tid for six weeks) was more effective than placebo (n = 375) at reducing HAM-D scores in outpatients with mild-to-moderate depression.11
Controversy remains about why the U.S. trials contradict the mostly positive European trials. Barrette points out in the last Alternative Medicine Alert update on SJW that the U.S. trials were performed at academic sites while the German studies generally used community physician practices. Most German trials enrolled patients with mild-to-moderate depression but few used DSM-IV criteria. The U.S. trials trained all raters extensively and tested for reliability (e.g., scoring videotaped vignettes). The U.S. trials used a higher cut-off for the depression scores, potentially enrolling more severely depressed subjects. However, two more recent European trials, by Philipp et al and Szegedi et al, demonstrated a benefit of SJW over placebo and at least an equal benefit of SJW to paroxetine, respectively. Each of these trials enrolled subjects with a similar baseline HAM-D score to the U.S. trials.12-14 Disparities may be the result of an overestimation of effect in the older smaller studies as well as variable efficacy of SJW in different patient populations.15
Systematic reviews published between 1996 and 2000 concluded SJW is more effective than older antidepressants in the management of mild-to-moderate depression.16-18 Earlier trials have been criticized for faulty methodology, including poorly defined entry criteria resulting in heterogeneous populations, small enrollment, inadequate blinding, use of nonstandard outcome scores, use of combination products or low doses of SJW and/ or standard antidepressants, and short duration of follow-up. Because a variety of commercial products have been used, the generalizability of these studies to other preparations of SJW is uncertain.1
Linde et al published the most recent and methodologically sophisticated meta-analysis (listed in the Cochrane database) addressing such limitations in 2005.15 They included 37 trials, including 26 comparisons with placebo (n = 3,320 patients) and 14 comparisons with synthetic standard antidepressants (n = 2,283 patient). This review only included randomized, double-blind studies that dealt with depressive disorders, used appropriate clinical outcomes for assessing depressive symptoms, and compared extracts of St. John’s wort with placebo or standard antidepressants. Of note, among the 30 trials excluded from this analysis were seven that had been included in previous versions of their own reviews.
Results of the placebo-controlled trials demonstrated significant heterogeneity. In trials restricted to patients with major depression, the combined response rate ratio (RR) for hypericum extracts compared with placebo from six large trials showed a small benefit 1.15 (95% confidence interval [CI] 1.02-1.29) and from six smaller trials a larger benefit 2.06 (95% CI 1.65-2.59). In trials not restricted to patients with major depression, the RR from six large trials was 1.71 (95% CI 1.40-2.09) and from five smaller trials was 6.13 (95% CI 3.63-10.38).
Trials comparing hypericum extracts and standard antidepressants were statistically homogeneous. Compared with selective serotonin reuptake inhibitors (SSRIs) and tri- or tetracyclic antidepressants, respectively, RRs were 0.98 (95% CI 0.85-1.12; six trials) and 1.03 (95% CI 0.93-1.14; seven trials).
Patients given hypericum extracts dropped out of trials due to adverse effects less frequently than those given older antidepressants (odds ratio [OR] 0.25; 95% CI 0.14-0.45). The same observation was noted, although it was not statistically significant, between hypericum extracts and newer antidepressants (OR 0.60, 95% CI 0.31-1.15).
The more recent placebo-controlled trials suggest that hypericum extracts have minimal side effects and that the effects are similar to standard antidepressants. Linde et al concluded that current evidence regarding hypericum extracts is “inconsistent and confusing.”19
Since the publication of the most recent meta-analysis by Linde et al, there have been two trials comparing extracts of SJW and SSRIs.
Szegedi et al published a trial designed to test whether SJW (hypericum extract WS5570) works as well as paroxetine in moderate-to-severe major depression.14 The study was a randomized, double-blind, double-dummy, reference-controlled, multicenter, non-inferiority trial. Included were 251 adult outpatients with acute major depression (total score 22 on the 17-item HAM-D scale) drawn from 21 psychiatric primary care practices in Germany. Each received 900 mg/d hypericum extract WS5570 divided three times a day or 20 mg paroxetine once a day for six weeks. After two weeks, initial nonresponders’ doses were increased to 1,800 mg/d hypericum or 40 mg/d paroxetine. The primary outcome measure was change in score on HAM-D from baseline to day 42. Secondary measures included change in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), CGIS, and Beck Depression Inventory. HAM-D scores decreased by 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value in the hypericum group and by 11.4 (SD 8.6) points, or 44.8% (SD 33.5%) of baseline value, in the paroxetine group. Intention-to-treat analysis and per protocol analysis showed statistical superiority of hypericum over paroxetine. The incidence of adverse events was 0.035 events per day of exposure for hypericum and 0.060 for paroxetine. The authors concluded that hypericum extract WS5570 was at least as effective as paroxetine and better tolerated in the treatment of moderate-to-severe major depression.
Bjerkenstedt et al compared SJW extract with fluoxetine and placebo in a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter, outpatient trial funded by Lichtwer Pharma, makers of LI160.20 Included were 163 adult outpatients with major depression (total score > 21 on the 21-item HAM-D scale) drawn from general practices in Sweden. Each received SJW extract LI160 300 mg tid, fluoxetine 20 mg qd, or placebo for six weeks. The primary outcome measure was change in score on HAM-D from baseline to week 4 (SJW vs. placebo) and to week 6 (hypericum vs. fluoxetine). Secondary endpoints included remission (HAM-D total score < 8) at week 4, MADRS, and CGI. HAM-D scores were reduced 35-40% during the four-week double-blind treatment without any significant between-group differences. At six weeks a total reduction of 48% was observed for both SJW and fluoxetine, but this portion of the trial was not placebo-controlled. Remission was the only secondary outcome measure for both hypericum (24%) and fluoxetine (28%) that was significantly superior to placebo (7%). The authors conclude that both active treatments failed to prove superiority over placebo in primary outcome measures, but that they both improved remission rates. SJW and placebo were significantly better tolerated than fluoxetine.
Systematic reviews of adverse effects of SJW were published in 2003 and 2004.21,22 In randomized trials, SJW was tolerated as well as placebo, significantly better than older antidepressants, and perhaps slightly better than SSRIs when taken as recommended. The most common side effects are mild gastrointestinal symptoms, skin reactions, fatigue, sedation, restlessness, dizziness, headache, and dry mouth.22 Observational studies suggest adverse events occur in 1-3% of patients. In a 2001 review of 8 million people taking recommended doses of SJW extracts, 95 adverse events were documented.23
Photosensitivity has been seen in animals grazing on SJW and several human cases of reversible photosensitivity to SJW have been reported. Hypericin has been confirmed as the cause of photosensitivity in a Phase I study of pure hypericin in HIV-positive adults, with severe phototoxicity occurring in 11 of 23 subjects.24 Other studies have not demonstrated phototoxic reactions in patients administered oral LI160.25
One case of reversible subacute polyneuropathy occurred on sun-exposed areas after four weeks of hypericum.26
Induction of hypomania and mania are known complications of antidepressant therapy, and cases of hypericum precipitating hypomania and mania have been reported.12,27-30
Rare cases of hypertension and tachycardia have been reported.31 However, blood pressure and heart rate were equivalent in 200 patients enrolled in a six-week study comparing SJW (1,800 mg/d) to imipramine (150 mg/d).32 One report describes a cardiovascular collapse during anesthesia in a healthy 23-year-old woman who had been taking SJW for six months.33
Anorgasmia has been reported in 25% of subjects taking 900-1,500 mg/d of SJW for eight weeks compared to 16% taking placebo and 32% taking sertraline.11 Reduced sperm motility has been reported in vitro with the use of SJW.34
A broad range of drug interactions has been described but the clinical relevance of many of these remains unclear (see Table). Perhaps the most clinically relevant interactions occur with cyclosporine (lowering serum cyclosporine concentration), other antidepressants, particularly the SSRIs (serotonin syndrome), antiretroviral therapy (reducing the concentration of protease inhibitors in HIV-infected patients), and coumadin-type anticoagulants (decreasing anticoagulation). There is concern that SJW may interfere with the efficacy of oral contraceptives (OCs).
SJW induces CYP 3A/3A4 apparently through upregulation of this enzyme by hyperforin.35,36 Thus, most interactions with SJW result in a lowered concentration of the second drug. In addition, evidence suggests that SJW also induces the intestinal transport protein P-glycoprotein, which may further lower plasma levels of drugs.
Cyclosporin is metabolized largely by CYP 3A4 and there are multiple case reports of kidney, heart, and liver transplant rejections and reduced cyclosporine serum levels in patients who received concomitant SJW. An observational study found that 30 kidney transplant recipients taking SJW had significant decreases in cyclosporine levels. These levels increased when SJW was discontinued.37
OCs are also metabolized in part by CYP 3A4 and there have been multiple case reports of breakthrough bleeding in women who use these and SJW.38 Several reports also describe unwanted pregnancies in women taking OCs and SJW.39 A randomized controlled trial, however, involving 18 healthy females (ages 18-35 years) treated with a low-dose OC (0.02 mg ethinylestradiol, 0.150 mg desogestrel) alone or combined with SJW extract (Jarsin LI160 300 mg bid) failed to demonstrate evidence of ovulation during combination treatment, but did show increased intracyclic bleeding episodes.40
Protease inhibitors and nonnucleoside reverse transcriptase inhibitors are also metabolized by CYP 3A4 and SJW has been demonstrated to decrease their serum concentrations probably by this mechanism, and perhaps through inducing drug pump P-glycoprotein.41-43
There is one report of a 42-year-old woman with decreased serum theophylline levels after concomitant ingestion of SJW 300 mg qd. Theophylline is metabolized by CYP 1A2. The woman was taking several other medications and smoking tobacco. However, upon discontinuing SJW her theophylline levels rose.44
Reductions in concentration of nifedipine and midazolam, which are metabolized by CYP 3A4, were reported in a human study.45
Warfarin is metabolized by CYP 2C9 and there are at least seven cases of lowered international normalized ratio (INR) in patients felt to be stable with concomitant use of SJW. Increases in warfarin dose or discontinuation of SJW led to INR returning to target values.38 It is believed this interaction may be due to induction of drug pump P-glycoprotein.41
One case report of cardiovascular collapse during anesthesia in a 23-year-old female taking SJW and one of delayed emergence from anesthesia in a 21-year-old female taking SJW have been published.46,47
Tricyclic antidepressant concentrations were reduced significantly in a 14-day open study of 12 depressed patients.48 These drugs are metabolized by multiple CYP enzymes.
Consistent with serotonin syndrome, anxiety, confusion, irritability, restlessness, dizziness, nausea, vomiting, and headache were reported in a case series of five elderly patients who started SJW while on stable doses of sertraline (four patients) and nefazodone (one patient).49 A similar interaction was reported in a 61-year-old woman and a 50-year-old woman taking paroxetine.50,51 A single case report described severe hypertension in a patient taking SJW who consumed aged cheese and red wine.52
Digoxin levels were reduced by about 25% in a 10-day controlled trial in patients concomitantly treated with SJW.53 It is felt this may be due to induction of the P-glycoprotein drug transporter.
Dosage and Formulation
Most studies used 300 mg given three times a day but doses have ranged from 500 mg to 1,800 mg daily. Several standardized ethanol and methanol extracts exist. Most products were formulated to contain 0.3% hypericin providing 2.7 mg/d hypericin when 900 mg hypericum is taken. Recently some manufacturers have begun standardizing to hyperforin (usually 2-5%). The continuing problem of standardization and purity was seen in a study of eight SJW products purchased in Germany (two are available in the United States).54 The products were found to contain “widely differing amounts” of hypericin and hyperforin. Some even demonstrated pronounced batch-to-batch variability. A review by an independent laboratory reported that among the 10 products selected for testing (two were immediately dropped from further testing because they lacked information about the part of the SJW used, an FDA labeling requirement), three failed testing for cadmium contamination, exceeding the cadmium limit established for medicinal plants by the World Health Organization by 100-1,000%. One of these also had lead contamination above the limit established by the state of California. A fourth product failed for suggesting a dose that was likely to be too low to be effective—less than one-quarter of the standard dose.55
The most stringent reviews of the literature on SJW continue to suggest benefit in the treatment of patients with mild-to-moderate depression and those with depressive symptoms not necessarily rising to the level of major depressive disorder (MDD). In more severe forms of MDD the evidence is unclear, and suggests only minor benefit at best. Numerous herb-drug interactions, some with significant clinical relevance, continue to be reported. Although adverse events have been reported, SJW appears to be better tolerated than older antidepressants and at least as well tolerated as SSRIs. Longer studies comparing SJW with newer antidepressants are warranted.
SJW may be a reasonable choice for short-term treatment of patients with mild-to-moderate depression and those with depressive symptoms not necessarily rising to the level of MDD who prefer to use a “natural” therapy. Although it has not demonstrated clear superiority over other antidepressants, SJW is relatively inexpensive and well-tolerated. Prescribers should familiarize themselves with the list of drug-herb interactions and carefully avoid any relevant combinations. All patients should be asked about their use of herbal products and dietary supplements. Because there is significant variability between SJW products available, it makes sense to recommend those utilized in positive clinical trials. There is little reliable evidence to support SJW use in moderate-to-severe depression and it should not be a first-line agent in these patients.
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24. Gulick RM, et al. Phase 1 studies of hypericin, the active compound in St. John’s Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med 1999;130:510-514.
25. Schempp CM, et al. Single-dose and steady-state administration of Hypericum perforatum extract (St John’s wort) does not influence skin sensitivity to UV radiation, visible light, and solar-simulated radiation. Arch Dermatol 2001;137:512-513.
26. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St John’s Wort. Lancet 1998;352: 1121-1122.
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30. Spinella M, Eaton LA. Hypomania induced by herbal and pharmaceutical psychotropic medicines following mild traumatic brain injury. Brain Inj 2002;16:359-367.
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34. Ondrizek RR, et al. Inhibition of human sperm motility by specific herbs used in alternative medicine. J Assist Reprod Genet 1999;16:87-91.
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36. Moore LB, et al. St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000;97:7500-7502.
37. Breidenbach T, et al. Profound drop of cyclosporine A whole blood trough levels caused by St. John’s wort (Hypericum perforatum). Transplantation 2000;69: 2229-2230.
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39. Schwarz UI. Unwanted pregnancy on self-medication with St John’s wort despite hormonal contraception. Br J Clin Pharmacol 2003;55:112-113.
40. Pfrunder A, et al. Interaction of St John’s wort with low-dose oral contraceptive therapy: A randomized controlled trial. Br J Clin Pharmacol 2003;56:683-690.
41. Cott JM. Herb-drug interactions: Focus on pharmacokinetics. CNS Spectr 2001;6:827-832.
42. De Maat MM, et al. Drug interaction between St John’s wort and nevirapine. AIDS 2001;15:420-421.
43. Piscitelli SC, et al. Indinavir concentrations and St John’s wort. Lancet 2000;355:547-548.
44. Nebel A, et al. Potential metabolic interaction between St John’s wort and theophylline. Ann Pharmacother 1999;33:502.
45. Smith M, et al. An open trial of nifedipine-herb interactions: Nifedipine with St John’s Wort, ginseng or Ginkgo biloba. Clin Pharmacol Ther 2001;69:86.
46. Crowe S, McKeating K. Delayed emergence and St John’s wort. Anesthesiology 2002:96:1025-1027.
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48. Johne A, et al. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John’s wort (Hypericum perforatum). J Clin Psycho-pharmacol 2002;22:46-54.
49. Lantz MS, et al. St. John’s wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol 1999;12:7-10.
50. Gordon JB. SSRIs and St. John’s Wort: Possible toxicity? Am Fam Physician 1998;57:950-953.
51. Waksman JC, et al. Serotonin syndrome associated with the use of St. John’s Wort (Hypericum perforatum) and paroxetine. J Toxicol Clin Toxicol 2000;38:521.
52. Patel S. Hypertensive crisis associated with St. John’s Wort. Am J Med 2002;112:507-508.
53. Johne A, et al. Pharmacokinetic interaction of digoxin with an herbal extract from St John’s wort (Hypericum perforatum). Clin Pharmacol Ther 1999;66:338-345.
54. Wurglics M, et al. Comparison of German St. John’s wort products according to hyperforin and total hypericin content. J Am Pharm Assoc (Wash) 2001;41:560-566.
55. St. John’s wort. Available at: www.ConsumerLab.com. Posted April 26, 2004. Accessed June 6, 2005.